Research in year 03 of this grant will be directed along two main lines: (1) Further investigation into molecular structures and conformations of a number of derivatives of the cyclophosphamide drugs. We have on hand several interesting compounds, some synthesized by Takamizawa's group and others synthesized by Struck's group in Alabama. Their successful structure determinations will be very useful in adding to our knowledge of stereochemical determinants of cyclophosphamide drug activity. (2) We have crystallized and will perform structure determinations of some of B.R. Baker's folic acid antagonists. Comparison of clinically useful tumor dihydrofolate reductase inhibitors with each other and with folic acid or its analogues, if they can be successfully crystallized, will be extremely useful in elucidating sterochemical parameters for design of new antifolate cancer drugs.